What Does Low-Intensity rTMS Do to the Cerebellum?

Abstract

Non-invasive stimulation of the human cerebellum, such as by transcranial magnetic stimulation (TMS), is increasingly used to investigate cerebellar function and identify potential treatment for cerebellar dysfunction. However, the effects of TMS on cerebellar neurons remain poorly defined. We applied low-intensity repetitive TMS (LI-rTMS) to the mouse cerebellum in vivo and in vitro and examined the cellular and molecular sequelae. In normal C57/Bl6 mice, 4 weeks of LI-rTMS using a complex biomimetic high-frequency stimulation (BHFS) alters Purkinje cell (PC) dendritic and spine morphology; the effects persist 4 weeks after the end of stimulation. We then evaluated whether LI-rTMS could induce climbing fibre (CF) reinnervation to denervated PCs. After unilateral pedunculotomy in adult mice and 2 weeks sham or BHFS stimulation, VGLUT2 immunohistochemistry was used to quantify CF reinnervation. In contrast to sham, LI-rTMS induced CF reinnervation to the denervated hemicerebellum. To examine potential mechanisms underlying the LI-rTMS effect, we verified that BHFS could induce CF reinnervation using our in vitro olivocerebellar explants in which denervated cerebellar tissue is co-cultured adjacent to intact cerebella and treated with brain-derived neurotrophic factor (BDNF) (as a positive control), sham or LI-rTMS for 2 weeks. Compared with sham, BDNF and BHFS LI-rTMS significantly increased CF reinnervation, without additive effect. To identify potential underlying mechanisms, we examined intracellular calcium flux during the 10-min stimulation. Complex high-frequency stimulation increased intracellular calcium by release from intracellular stores. Thus, even at low intensity, rTMS modifies PC structure and induces CF reinnervation.

In vitro Magnetic Stimulation: A Simple Stimulation Device to Deliver Defined Low Intensity Electromagnetic Fields

“…Since our previous studies suggest that low intensity magnetic stimulation has less effect on normal vs. abnormal neural circuits (Rodger et al, 2012; Sykes et al, 2013; Makowiecki et al, 2014), we lesioned our explants to create a denervation/reinnervation model. Cerebellar plates were separated from their explant brainstem at DIV 23 (equivalent to P17), placed adjacent to intact cerebellar tissue of a second explant (co-culture; Figures 1A,D,E and 2D ) and stimulated to induce reinnervation (Morellini et al, 2015). …”

Rhythms and blues: modulation of oscillatory synchrony and the mechanism of action of antidepressant treatments

“…For example, antidepressant medications, ECT, and rTMS have all been reported in human and animal models to increase the expression and signaling of brain‐derived neurotrophic factor (BDNF, a trophic factor that mediates neuroplasticity) in the hippocampus and cortex . Repetitive TMS has been demonstrated to enhance neuroplasticity in cortical and corticospinal systems, possibly mediated through changes in expression of BDNF . Increased BDNF (either through direct injection into the brain or overexpression through transgenic manipulation) can produce changes in behavior similar to those induced by antidepressant medications .…”

“…[28][29][30] Repetitive TMS has been demonstrated to enhance neuroplasticity in cortical and corticospinal systems, possibly mediated through changes in expression of BDNF. [30][31][32] Increased BDNF (either through direct injection into the brain or overexpression through transgenic manipulation) can produce changes in behavior similar to those induced by antidepressant medications. 33,34 Increased BDNF expression may be induced by epigenetic processes, such as chromatin remodeling and histone methylation; alterations in intracellular signaling, such as phosphorylation of transcription factors affecting gene expression; and posttranslational modification of proteins.…”

An observational study of balance and proprioception function in patients with spinocerebellar ataxias type 3

“…Impairments in the activation function of the synaptic transmission between the climbing bres and Purkinje cells inhibits cortical motor activation via a complex neural pathway involving the dentate nucleus, which could be related to abnormal postural sways in SCA3 patients [37][38] . Previous studies have demonstrated that cerebellar transcranial magnetic stimulation (TMS) is capable of facilitating motor cortical activation via modulation of Purkinje cell excitability [39][40] . Therefore, TMS is recommended to activate the function of the cerebellar to improve balance.…”